Derivatives of hydroxycycloalkylalkylbenzoylaliphatic acids and methods for producing same



Patented Jan. 1, l$52 I IERIVATIVES F HYDROXYCYCLOALKYL- ALKYLBENZOYLALIPHATIC ACIDS AND -METHODS FOR PRODUCING SAME Robert R. Burtner, Skokie, 111., as signor to G. D. S'earle a 00., Chicago, 11]., a corporation of Illinois No Drawing. Application March 18,1950.

SerialNo. 150,549

1 This invention relates in general tocycloaikylalkylbenzoylaliphatic acids containing hydroxyl and alkoxyl substituents inthe phenyl nucleus, and to methods for the production of such compounds. concerned with compounds of the general structural formula R-A ox Y wherein R is a cycloalkyl radical, X is a hydrogen or lower alkyl radical, Y is a hydrogen, alkyl, hydroxyl or alkoxyl radical, A and B are lower alkylene groups and Z is hydrogenor one equivalent of a. cation.

Inthe foregoing structural formula, R represents alicyclic radicals such as cyclobutyl, cyclopentyl, cyelohexyl, cycloheptyl, as well as alkyl derivatives of such radicals. X represents hydrogen or a lower alkyl radical such as methyl, ethyl, propyl, isopropyl, butyljisobutyl, secondary-butyl, tertiary-butyl and the like. Y represent a member of the class consisting of'hydrogenfhydroxyl, lower alkyl groups of the foregoing'type, and lower alkoxyl radicalssuch as methoxy; ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary-butoxy; tertiary-butoxy and the like. The alkylene group represented by A consists of a bivalent aliphatic hydrocarbon radical containing one to eight carbon atoms'in a straight or branched chain arrangement such as methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene and polymethylene from trimethylene to octamethylene.

More particularly, this invention is reclaims. (o1. zen- 520) The; radical B may likewise represent unsaturatedj'aliphatic hydrocarbon radicals containing oneor two double bonds, such as vinylene and allyl-e'ne. "The alkyle'ne group B'is a member of the same class of bivalent aliphatic hydrocarbon radicals, excluding only methylene. Z representsone equivalent of a cation such as hydro gen, an alkali metal ion, an earth alkali metal ion', an ammonium iori and an amine ion.

The object of. this invention is to provide novel chemical "s'ubstances of the typeindicated above and-'to'pr'cvide simple and economical methods "duo g such substancesg'l lurther, it is the the invention to provide feasible synetliods for the manuiacture of the fore- 'g oi' ng substances from readily a ailab e sta tin materials?" The compounds 'of the invention are useful as therapeutic agents and as intermediates in chemical synthesis. f Thus, certain ofthem are efl'ective 'as choleretic agents. For this purpose, they may be administered in the form. of the free acids or in the form of water soluble salts. Further, certain of these compounds are useful asparasiticidal agents.

The compounds of this invention are prepared by reacting an alkoxyphenylalkylcycloalkane of the following generali'ormula with a dibasic aliphatic acid anhydride or halide derived from a 'dibasic acid of the following formula noose-B40011 with a Friedel-Crafts type catalyst, generally in an inert organic solvent. Among such catalysts are anhydrousxaluminum chloride, anhydrous ferric chloride, stannic chloride, boron trifiuoride, zinc chloride, hydrogen fluoride, sodiumaluminum chloride and similar substances. The inert solvents are organic liquids having chemical reactivities lower than those of the foregoing ethers' and include nitrobenzene, carbon disulfide, chlorobenzene, tetrachloroethane, and related substances. Among the dibasic acid anhydrides and halides which can be used in preparing these compounds are succinic, glutaric, adipic, pimelic, suberic, sebacic, maleic, fumaric, methylsuccinic, ethylsuccinic, alpha-methylglutaric, beta-methylglutarlc, alpha-methyladipic and related dibasic acids. The mono-ester acid chlorides of these acids-may likewise be employed. The alkoxyphenylalkylcycloalkanes are conveniently obtained by-the alkylation of the corresponding 'hydroxyphenylalkylcycloalkanes which are prepared by the process of R. H. Talbot and R. Adams, J. Am. Chem. Soc. 49, 2040; 192.7. v l l The alkoxyl compounds obtained in the Friedel-Craits reaction may be dealkylated by the usual methods such as by the use of aluminum chloride or such hydrohalic acids as hydrobromic or hydriodic acid.

Salts oft-the acids which comprise this invention are [generally prepared by reacting the acids with an aqueous solution of alkali or of an organic amine such as a lower alkyl, dialkyl, or trialkyl airline or corresponding alkanol amine,

fllteringths'olution so formed and evaporating the filtrate to dryness, generally under low pressure and at low temperature. In certain in stances the salts of the acids of this invention may be obtained in crystalline form by salting 6 d..$alts with,.a simple inorganic .salt such as sodium chloride; sodium sulfate or ammonium chloride. Alternatively salts of the acids of this invention can be prepared by reacting an. alcoholic solution of the acid with an alcoholic pressure.

should be understood, however, that :thesecan" To a suspension of 350 parts of 2,4-dimethoxy- .benzvlcyclopentane and 1 60 parts of succinic anhydride in 1920 parts of nitrobenzene 43.7 'parts of anhydrous aluminum chloride are added portionwise with goodagitation. During the addition and for an additional 15 minutes the temperature is maintained at 0 -to'.5, eflicient agi V tation being'used throughout. Stirring at .room temperature is continued for threehours. Hvdrolysis is effected by quenching with dilute hy-'- dro hloric acid and ice. The mixture is steam d stilled to remove solvent and the aqueous residue chilled. The semi-solid crude product is taken .up in 2000 parts .01 water containing 30 parts of sodium carbonate at about 90. The hot solution is cooled, washed once with ether and then heated to remove all ether residues. After cooling the solution is acidified, the sand colored acid is filtered, rinsed with? Water and dried. 265 parts of the crude beta-(2,4-dimethoxys5ecyclopentylmethylbenzoyl)propionic acid of the struc ture OCH: CHPCH: I

are obtained. Two recrystallizations' from five volumes ofmethanol, using charcoal as a clarifying agent, give pure, colorless crystals melting at about '1 59-1 '60.

EXAMPLE 2 is collected on a filter, rinsed with water and dried. 60 parts of crude beta-(2,4-dihydrory- 5-cyclopentylmethylbenzoyl)propionic acid are thus obtained which, after crystallization from .'lllparts of glacial acetic .acidusing. charcoal as ga. clarifying agent, yield-- 42 ;parts; of pure, colorless crystals melting at about 201. In the ferric chloride test, a strong purple color is obtained.

EXAMPLE 3 Beta- 2-methomy-5-cyclohemylethylbenzoyl propionic acid Cyclohexylacetyl chloride is condensed with 'anisole'in nitrobnz ene using aluminum chloride as a catalyst-in order to prepare p-cyclohexyl- .acety1anlsole, -which boils at 1'35-136 at 0.3 mm. Clemmensen reduction in a mixture of hydrochloric acid and toluene yields p-cyclohexylethylanisole of a boiling point of 128-130 at 0.8 mm. pressure. l

300 parts of pcycloheirylethylanlso'le and 140.

' parts of succinic anhydride suspended-in I800 parts-of nitrobenzene 'are reacted with good agi tation at 0 to 5 with3'75 parts -'of anhydrous aluminumchloride which is added portionwise. After completion of the addition, stirring all-"0 is continued for one hour. The mixture-is then permitted to warm up to room temperature and, after 15 hours standing, is quenched with dilute hydrochloric acid and ice.' The solvent is removed by steam distillation andthe aqueous residue is chilled. The dark, tacky crude acid is taken up in 1000 parts of water containing 30 parts of sodium carbonate at-about The hotsolution is filtered, cooled, washed once with ether and the residual ether removed by heating.

The solution is thenchilled, and upon lacidifica tion a light brown oil separates which becomes granular on standing. precipitate of .the beta -(2 methoxy 5 --cyclohexylethylbenzoyl) propionic acid is collected on a filter, rinsed with water, dried. and then recrystallized from cyclohexane. The colorless crystals meltat aboutlOB.

EXAMPLE 4 Beta- (2-hydroxy-5-cyclohemylethylbenzoyl) propionic acid V 5 I Beta-l3,4-dimethomy-5-czlclohexylmethllle 'benzoytlpropionic acid Qyclohexyl magnesium bromide i reacted with ,3-dimethoxybenzaldehyde to produce 2,3-dimethoxyphenyl cyclohexyl carbinol. The latter is oxidized to the 2,3-dimethoxyphenyl cyclohexyl ke'tone which on Clemmensen reduction yields 2,3dimethOXybenzylcyclohexane, which boils at ;.136" at 0 .3 mm. pressure.

536 partsfof anhyd ou uminu chloride are added portionwise at 0' to 5 .to a stirred suspension of 470 parts of 2 ,3-dimethoxybenzylcyclo. hexane and 200 parts of succinic anhydride in:

5 2400 parts of nitrobenzene. After completion of the addition, stirring is continued for 20 minutes at and then at room temperature for 4 hours. The product is worked up as in Example 3. Upon acidification a dark yellow, viscous oil is obtained which granulates readily on standing. The crude acid is triturated with water, collected on a filter, rinsed with water and dried. Crystallization from 70% acetic acid using charcoal as a clarifyingagent and then from methanol yields pure, colorless beta-(3,4-dimethoxy-5-cyclohexylmethylbenzoylipropionic acid, which melts at about 144.

EXAMPLE 6 Beta-(3,4-dihydroxy-5-cycl0hexylmethylbenzoyl) propionic acid EXAMPLE 7 Beta- (2,4 -dimetho:ry-5 -czlcloheasylmethylbenzoyl) propionic acid 665 parts of 2,4-dimethoxybenzylcyclohexane (obtained by methylation of cyclohexylmethylre- I sorcinal) and 290 parts of succinic anhydride suspended in 3600 parts of nitrobenzene are reacted at 0 to'3 under efilcient agitation with 777 parts ofaluminum chloride which is added portionwise. After completion of the addition, stirring is continued for minutes at 0 and then at room temperature for 4 hours. The crude acid is obtained by the method described in Example 5. Crystallization from acetic acid yields pure, colorless needles, melting at about 174.

EXAMPLE 8 Y Beta: 2,4 -dihydro:cy-5 -cycloheatylmethylbenzoyl) propionic acid Demethylation of the beta-(2,4-dimethoxy-5- cyclohexylmethylbenzoyl) propionic acid, obtained as in Example 7, with hydriodic acid and acetic anhydride gives the dihydroxy-acid, which melts at 212 with decomposition. The ferric chloride test gives a strong purple color.

EXAMPLE 9 Beta- (2,5 -dz'methomy-4-cycZohe:rylmethyZ- benzoybpropionic acid 1 By areaction of hydroquinone dimethyl ether and hexahydrobenzoyl chloride with aluminum chloride in nitrobenzene the 2,5-dimethoxyphenyl oyclohexyl ketone is obtained which boils at 142-144 at 0.1 mm. Clemmensen reduction yields 2,5-dimethoxybenzylcyclohexane, boiling at 115116 at 0.25 mm..pre ssure. 340 parts of this 2,5-dimethoxybenzylcyclohexane and 150 parts of succinic anhydride suspended in 1800 parts of nitrobenzene are reacted at 0 to 3 under eflicient agitation with 402 parts of anhydrous aluminum chloride which is added portionwise. When the addition is complete, stirring is continued for minutes at 0 and then at 20 to 25 for 5 hours. The product is worked up in the usual manner. f-I'heacrude beta (2,5 dimethoxy 4 cyclohexylmethylbenzoyhpropionic acid is purified by crystallization from methanol using charcoal as a clarifying agent. The colorless crystals melt at about 124.

hours at 20 to 25.

EXAMPLE 10 I new (2,5-dihydroary-4-cyclohexylmcthylbenzoyl) propionic acid Beta- (4,5 -dimethoxy-2-cyclohexylmethylbenzoyl) propionic acid 7 Interaction of hexahydrobenzoyl chloride and veratrole in the presence of aluminum chloride in nitrobenzene gives 3,4-dimethoxybenzoylcyclohexane (boiling at -l62/0.3 mm), which on Clemrne'nsen reduction yields 3,4-dimethoxybenzylcyclohexane (boiling at 121-122/0.25 mm.). 570 parts of this 3,4-dim-ethoxybenzylcyclohexane and 250 parts of succinic anhydride suspended in 3000 parts of nitrobenzene are reacted at 0 to 3 under efiicient agitation with 670 parts of anhydrous aluminum chloride which is added portionwise. After completion of the addition, stirring is continued for 30 minutes at 0 and for 4 Hydrolysis, steam distillation of the solvent and extraction with hot alkali as described in Examples 1 and 3 gives beta-(4,5- dimethoxy 2 cyclohexylmethylbenzo yl)propionic acid. Crystallization from methanol with the aid of charcoal as a clarifying agent yields pale yellow needles, melting at about 148.

EXAMPLE 12 Beta-(4,5-dihydroxy-Z-cyclohexylmethylbenzoyl) propionic acid The acid described inExample 11' is dlemethylated by the procedure of Example 2. Recrystallization from 60% acetic acid produces crystals melting at Bl-132. A dark green color is obtained in the ferric chloride test.

1 EXAMPLE 13 Beta- [2,4-dimethoxy-5- beia-cycloheacylthyl) benzoyllpropionic acid 570 parts of 2,4-dimethoxyphenethylcyclohexane (obtained by methylation of beta-cyclohexylethylresorcinol) and 240 parts of succinic anhydride suspended in 2760 parts of nitrobenzene are reacted at 0 to 5 under efilcient agitation with 643 parts of aluminum chloride which is added portionwise. After completion of the addition, stirring is continued for 20 minutes at 0 and then at room temperature for 4 hours. The crude acid is obtained by the method described in Example 3. Crystallization from acetic acid usingcharcoal as a clarifier yields pure beta-(2,4- dimethoxy 5 cyclohexylethylbenzoyl) propionic acid which melts at about This compound has the structural formula cH-cmom CHzCHz mo -oom U OOH2CH2-C O OH EXANIPLE 14 benzoyllpropionic acid f Demethylation of the acid described in Exam ple 13 is carried out, by the procedure givenin Example 2. The crude. acidiisrecrystallized from methanol and pure, colorless crystals. are obtained which melt at about 1w. A: deep. red color is observed in the ferric chloride test.

Beta- [2,4-dz'mthoxy-5- omega cyclohexyl amyl) benzoyl] propionic acid Delta-cyclohexylvaleric acid reacts with resorcinol under the influence of zinc chloride to produce the deltacyc1ohexylbutyl 2,4-dihyclroxyphenyl ketone which, reduced with zinc and hydrochloric acid, yields omega-(2,4Pdihydroxyphenyl) pe'ntylcyclohexane. melting at about 89. The latter is dimethylated with diniethyl sulfate. 1008 parts of the 1-(omega-cyclohexylpentyl) -2,- -dimethoxybenzcne thus obtained (12 1.5142) and 350 parts of succinic anhydride are. suspend- H2O OCHa iocnicnwc OH The crystals melt at 150.5%

EXAMPLE 16 Beta- 2,4-dz'hydro'xy-5- (omega-cyclohexylamyl) benzoyllpropionic' acid The acid described in Example 15 is demethylated by the procedure given in Example 2. The crude product is waxy, but on crystallization from methanol with the use of charcoal the crystalline beta-2,4-dihydroXy--(omega-cyclohexylamyDben'zoyl propionic acid is obtained in pure form. The acid melts at about 145 and gives a deep amethyst color with ferric chloride.

EXAMPLE 1'? D'elta-(Z-zsopropyl 4 methory 5 hexahydro' benzyl-benzoylwaleric acid 49 parts of 2-hexahydrobenzyl-5-isopropylanisole and 26 parts of adipic anhydride are suspended in a mixture of 100 parts of nitrobenzene and 400 parts of tetrachloroethane. To this suspension, maintained in a state of strong agitation throughout the reaction, 56 parts of-aluminum chloride are added portionwise. The temperature is kept at 0 to 5 during the addition and for two hours longer. After standing at room temperature for 12 hours, the addition complex is hydrolyzed by quenching with dilute hydrochloric acid and ice. The mixture is steam distilled to remove the solvent and the aqueous residue is chilled and filtered. The resulting delta-(2-isopropyl-a-methoxy- 5 -hexahydrobenzylbenzoyl) valeric acid. is purified by. the method described in Examples; Recrystallization from a mixture of benzene and petroleum other results in the. formation of colorless needles which are moderately soluble in dilute alkali.

i 8 I- claim: 1*. A compound of the structural formula wherein R is a cycloalkyl radical of no more than six carbon atoms, X is a member of the class consisting of hydrogen and lower alkyl radicals, Y is a member of the class consisting of hydrogen, lower alkyl, hydroxyl and lower alkoxyl, A and B are bivalent aliphatic hydrocarbon radicals of no more than six carbon atoms and Z is a member of the class consisting of hydrogen and one equivalent of a cation.

2". The process of producing a beta-cyclohexylmethyldimethoxybenzoylpro'pionic acid of the structural iormula OCH:-

which comprises reacting a hexahydrobenzyldimethoxybenzene with succinic anhydride in the presence of anhydrous. aluminum chloride .and separating the acid formed.

3. The process of producing a beta-cyclohexylmethyldihydroxybenzoylpropionic acid of the structural formula,

which comprises reacting dimethoxybenzylcyclohexane with succinic acid in the presence of anhydrous aluminum chloride, separating the acid formed, demethylating said acid with a hydrohalic acid and separating the demethylated acid thus formed.

4. A compound of the structural formula wherein R is a cycloalkyl radical of no more than six carbon atoms, X is a lower alkyl radical, Y is a lower alkoxyl radical, A and B are bivalent aliphatic hydrocarbon radicals of no more than six carbon atoms and Z is one equivalent ofa cation.

5. A compound ofjthe' structural formula.

R -A O C H;

wherein Ris a cycloalkyl radical of no more than sixcarbon atoms, Y is a lower alkoxyl radical, A and B are bivalent aliphatic hydrocarbonradic'als or no more than six carbon atoms and Z is one equivalent of a cation. r

macaw t. A compound or the structural itrmms C OB-O O Z 0cm r s- OCHi wherein R is a cycloalk-yl radical of no more than six carbon atoms, A and B are bivalent aliphatic hydrocarbon radicalsoi' no more than six carbon atoms and Z is one equivalent of a cation. l

7. A compound of the structural formula wherein R is a cycloalkyl radical of no more than six carbon atoms, X is a lower alkyl radical, Y is a lower alkoxyl radical, A is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation.

8. A compound of the structural formula C O-GHr-CHr-C 0 OZ OCH;

wherein R is a cycloalkyl radical of no more than six carbon atoms, X is a lower alkyl radical, A is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation.

9. A compound of the structural formula OCH:

wherein R is a cycloalkyl radical of no more than six carbon atoms, A is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation.

10. A compound of the structural formula oo-cm-cm-cooz QHzCH: 6 B20 OIL-A OCH:

OCH:

wherein A is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation.

11. A compound of the structural formula R-CH OX wherein R is a cycloalkyl radical of no more than six carbon atoms, X is a lower alkyl radical, .Y is a lower alkoxyl radical, B is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation. 76

12. A compound of the structural formula A wherein R is a cycloalkyl radical of no more than six carbon atoms, B is a bivalentaliphatic hydrocarbon radical-oi? no more than six carbon atoms and Zis oneequivalent of ab ation.

13. A compound of the structural formula co -n-co'oz con,

wherein B a bivalent aliphatic hydrocarbon radicalof no morethan six carbon atoms and Z' is one equivalent of a cation. 4

14. A compound of the structural formul C OCH2-CH:C o o z CH-G H2 OCH: CH CEI OCH;

wherein Z is one equivalent of a cation.

15. A compound of the structural formula Bags...

wherein R is a cycloalkyl radical of no more than six carbon atoms, A and B are bivalent aliphatic hydrocarbon radicals of no more than six carbon atoms, Z is one equivalent of a cation, and n is an integer smaller than 3,

16. The process of producing a compound of the formula co-n-cooz B-A OX wherein R. A, X and Y have the foregoing meanings. with a member 01' the class consisting of acid anhydrides and acid halides derived from a dibasic aliphatic acid of the formula HOOCBCOOH in the presence of a Friedel-Crafts catalyst in an inert solvent and separating the acid formed.

11" 17. The process of claimv 16, wherein the catalyst is anhydrous aluminum chloride.

18. A compound of the structural formula wherein A and B are bivalent aliphatic hydrocarbon radicals of no more than six carbonatoms and Z is one equivalent of a cation.

19. A compoiind of the structural formula wherein A is a bivalent aliphatic hydrocarbon radical of no more than six carbon atoms and Z is one equivalent of a cation.

20. 'l he'aeid qfzthe .t mule O CHI OCH:

21. The acid of the formula OGH:

No references cited.

' mm-ewe 

1. A COMPOUND OF THE STRUCTURAL FORMULA 